Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to isoindole derivatives, and more particularly to 5-(hydroxymethyl)oxazolidine-2-one derivatives which are substituted at the 3 position by an indazole, benzisoxazole or benzisothiazole ring system, to a process for their preparation and to their application in therapy.
• the compounds of the invention correspond to the general formula (I) ##STR1## in which: X represents an oxygen atom, a sulphur atom or a group NR, R being a hydrogen atom or a linear or branched C 1 -C 4 alkyl chain,
• R 1 represents a hydrogen atom or a methyl group
• R 2 represents:
• R 3 O represents alternatively a hydrogen atom, or a benzyl group which is optionally substituted with a halogen atom or with a nitro or methylenedioxy group, or represents a methoxyethyl, butyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-hydroxybutyl or 4,4,4-trifluorobut-2-enyl group, or (ii) a group --CH ⁇ CH--R 4 or --CH 2 --CH 2 --R 4 , in which R 4 represents a hydrogen atom or a phenyl, 3,3,3-trifluoropropyl or 3,3,3-trifluoro-2-hydroxypropyl group.
• the compounds of formula (I) comprise one or two asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These various forms and their mixtures, including the racemic mixtures, are part of the invention.
• Preferred compounds are those for which:
• X represents an oxygen atom, a sulphur atom or a group NR, R being a hydrogen atom or a linear or branched C 1 -C 4 alkyl chain,
• R 1 represents a methyl group or a hydrogen atom
• R 2 represents a group R 3 O in which R 3 represents alternatively a hydrogen atom, or a benzyl group which is optionally substituted with a halogen atom or with a nitro or methylenedioxy group, or represents a methoxyethyl, butyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-hydroxybutyl or 4,4,4-trifluorobut-2-enyl group,
• X represents an oxygen atom, a sulphur atom or a group NR, R being a hydrogen atom or a linear or branched C 1 -C 4 alkyl chain,
• R 1 represents a methyl group or a hydrogen atom
• R 2 represents a group --CH ⁇ CH--R 4 or --CH 2 --CH 2 --R 4 , in which R 4 represents a hydrogen atom, or a phenyl, 3,3,3-trifluoropropyl or 3,3,3-trifluoro-2-hydroxypropyl group,
• X represents an oxygen atom
• R 1 represents a methyl group or a hydrogen atom
• R 2 represents:
• R 3 O represents alternatively a hydrogen atom, or a benzyl group which is optionally substituted with a halogen atom or with a nitro or methylenedioxy group, or represents a methoxyethyl, butyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-hydroxybutyl or 4,4,4-trifluorobut-2-enyl group, or
• X represents an oxygen atom
• R 1 represents a methyl group or a hydrogen atom
• R 2 represents alternatively a hydroxyl group, or a phenylmethoxy group which is optionally substituted with a halogen atom or with a nitro or methylenedioxy group, or represents a 4,4,4-trifluorobutoxy group or a 4,4,4-trifluoro-3-hydroxybutoxy group,
• the compounds of formula (I) in which R 1 is a methyl group and R 2 is a group OR 3 can be prepared according to the process represented in scheme 1. According to this process, the isoindole derivative of formula (II) is treated with one of the 4(R) or 4(S) isomers of 4-methoxymethyl-1,3-dioxolan-2-one of formula (IIIa) in the presence of potassium carbonate in order to obtain the 5(S) or 5(R) isomer of the compound of formula (Ia) according to the invention.
• the compounds of formula (I) for which X represents an NH group can be prepared from the compounds of formula (Ic) in which X represents an NCH 3 group by demethylation with the aid of benzoyl peroxide.
• the compounds of formula (I) in which R 1 is a methyl group and R 2 is a group --CH ⁇ CH--R 4 or a group --CH 2 --CH 2 --R 4 can be prepared according to the process represented in scheme 2.
• the compound of formula (Ib) according to the invention is treated with trifluoromethanesulphonic anhydride.
• the compound of formula (IV) thus obtained is reacted with tributylvinyl tin in the presence of lithium chloride and tetrakis(triphenylphosphine)palladium.
• the compound of formula (Id) according to the invention is then treated with ozone, and then with dimethylsulphide in dichloromethane, and the compound of formula (V) obtained is reacted with a triphenylphosphonium iodide of formula R 4 CH 2 PPh 3 +I - in which R 4 is defined as in formula (I) above, with the exception of the meaning hydrogen, in the presence of potassium carbonate.
• the compound of formula (Ie) according to the invention in which R 4 is defined as above is then reduced with hydrogen in the presence of a catalyst in order to obtain the compound of formula (If) according to the invention in which R 4 is defined as above.
• X is as defined in formula (I) above.
• the compounds of formula (I) in which R, is a hydrogen atom and R 2 is a group OR 3 , where R 3 is defined as in formula (I) above, can be prepared according to the process represented in scheme 3.
• the compound of formula (II) is treated with one of the 4(R) or 4(S) isomers of 4-phenylmethoxymethyl-1,3-dioxolan-2-one (IIIb) in the presence of potassium carbonate in order to obtain the 5(S) or 5(R) isomer of the compound of formula (VI).
• the isomer of formula (VI) is debenzylated by catalytic hydrogenation to give the 5(S) or 5(R) isomer of the compound of formula (Ib) as defined above.
• R 3 is defined as in formula (I) above, with the exception of the meaning hydrogen, and Y is a leaving group such as a chlorine or bromine atom or a tosyloxy group, to give the 5(S) or 5(R) isomers of the compounds of formula (Ic) according to the invention in which R 3 is defined as above.
• X is defined as in formula (I) above.
• the compound of formula (II) is prepared according to the process represented in scheme 4. According to this process, 2-fluoro-4-hydroxybenzonitrile is treated with benzyl bromide in the presence of potassium carbonate. The 2-fluoro-4-phenylmethoxybenzonitrile thus obtained is subsequently treated by three different routes depending on the meaning of X:
• Each of these routes leads to the preparation of a compound of formula (VII) in which X represents an oxygen atom, a sulphur atom or a group NR, R being a linear or branched C 1 -C 4 alkyl chain.
• the compound of formula (VII) is treated with ethyl chloroformate in the presence of sodium hydrogen carbonate to give the compound of formula (II) in which X is defined as above.
• the 4(S) isomer of the compound of formula (IIIa) is a known compound whose preparation is described in the patent EP-0 511 031. Its 4(R) isomer is prepared according to the same method from (R)-2,2-dimethyl-1,3-dioxolane-4-methanol.
• the 4(S) isomer of the compound of formula 4(R)-phenylmethoxymethyl-1,3-dioxolan-2-one (IIIb) is a known compound whose preparation is described in Helvetica Chimica Acta, 66, 1210-1240 (1983). Its 4(R) isomer is prepared according to the same method from (R)-2,2-dimethyl-1,3-dioxolane-4-methanol.
• 420 ml of demineralized water and 420 g (10.5 mol) of sodium hydroxide pellets are introduced into a 6-liter reactor fitted with a condenser, a temperature probe and a dropping funnel.
• 567 g (4.50 mol) of dimethyl sulphate are then added over 50 minutes while maintaining the temperature below 30° C.
• a mixture of 496 g of the product obtained in the preceding stage in 220 ml of demineralized water is heated to 60° C. with stirring and then 1.5 ml of 36% hydrochloric acid are added. Heating is maintained for 40 minutes and then the medium is adjusted to pH 8-9 by addition of 19 ml of triethylamine.
• the solvent is evaporated under a pressure of 5.2 kPa and at a temperature lower than 70° C. and then the residue is distilled at 61° C. under a pressure of 13 Pa. 246 g of product are obtained.
• the ethanol formed during the reaction (mass temperature: 95° to 112° C.; column temperature: 82° to 78° C.) is distilled for 2 hours and then the mixture is cooled and distilled under a pressure of 13 Pa in order to separate off the excess diethyl carbonate. 267 g of product are obtained.
• the residue is purified on a silica column with a 50:50 mixture of ethyl acetate and cyclohexane.
• the product is isolated in the form of an oil which crystallizes and which is triturated in diisopropyl ether. 1.5 g of product are obtained.
• a stream of ozone at -40° C. is passed for 2 hours into a solution of 8.0 g (0.029 mol) of (R)-5-(methoxymethyl)-3-(6-ethenyl-1,2-benzisoxazol-3-yl)oxazolidin-2-one in 210 ml of dichloromethane, then the ozone is driven off with a stream of argon, and 10.7 ml (0.15 mol) of dimethyl sulphide are added. The mixture is stirred for 3 hours while allowing the temperature to return to ambient temperature, and then the solvent is evaporated off under reduced pressure. By chromatography of the residue on a silica column with a mixture of 30% ethyl acetate in cyclohexane, 5.0 g of product are obtained.
• a mixture of 13.2 g (0.058 mol) of 2-fluoro-4-(phenylmethoxy)benzonitrile and 1.85 g (0.058 mol) of sulphur in 15 ml (0.58 mol) of ammonia and 50 ml of methylglycol is brought to 100° C. in an autoclave over 5 hours.
• the methylglycol is subsequently evaporated off under reduced pressure.
• the mixture is taken up in dichloromethane, the insoluble material is filtered off, and then the solvent is evaporated off under reduced pressure.
• the product is purified by chromatography on a silica column with cyclohexane and ethyl acetate in proportions of 60:40. Subsequently, a second purification by chromatography on a silica column with a mixture of diisopropyl ether and methanol in proportions of 99:1 leads to 1.7 g of product.
• R and/or S refers to the oxazolidinone heterocycle
• 5R and/or 5S refers to the chain R 2 .
• the compounds of the invention formed the subject of pharmacological tests permitting the determination of their inhibitory power with respect to monoamine oxidase A and monoamine oxidase B.
• the MAO-A and MAO-B activities in vitro were measured using a rat brain homogenate as enzyme source according to the method described by C. Fowler and M. Strolin-Benedetti in J. Neurochem, 40, 1534-1541 (1983).
• the reaction is started by the addition of 14 C!serotonin ( 14 C!5HT, final concentration 125 ⁇ M) to measure the MAO-A activity or of 14 C!phenylethylamine ( 14 C!PEA, final concentration 8 ⁇ M) to measure the MAO-B activity, in a final volume of 500 ⁇ l.
• the reaction is terminated by addition of 200 ⁇ l of 4N hydrochloric acid.
• the radioactive metabolites obtained from the oxidative deamination are then separated from the unconverted substrate by extraction into an organic phase, and are quantified by counting the radioactivity.
• the inhibitory activities with respect to MAO-A and MAO-B are given, respectively, by the inhibition constants Ki (MAO-A) and Ki (MAO-B).
• the Ki (MAO-A) values vary between 15 nM and more than 1 ⁇ M and the Ki (MAO-B) values vary between 1 nM and more than 1 ⁇ M.
• Certain compounds of the invention are selective inhibitors of MAO-B, it being possible for the ratio Ki(MAO-A)/Ki(MAO-B) to be of the order of 10 3 .
• the compounds of the invention can be used for the preparation of drugs which are selective inhibitors of MAO-B or mixed inhibitors of MAO-A and MAO-B, these drugs finding their therapeutic application, in particular, in the treatment of depressive states of any kind, senile depressive psychoses, hypobulia, social phobias, mood disorders, in the improvement of general cerebral performance, in the prevention or treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and all memory disorders, in anxiety, in panic attacks, in the treatment of dependency and withdrawal in connection with the consumption of tobacco, alcohol and/or narcotics, and loss of appetite.
• drugs which are selective inhibitors of MAO-B or mixed inhibitors of MAO-A and MAO-B, these drugs finding their therapeutic application, in particular, in the treatment of depressive states of any kind, senile depressive psychoses, hypobulia, social phobias, mood disorders, in the improvement of general cerebral performance, in the prevention or treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and all
• the compounds of the invention can be provided, in combination with excipients, in the form of compositions formulated for oral, parenteral or rectal administration, for example in the form of plain tablets, coated tablets, capsules, solutions, suspensions or suppositories.
• the daily dose of active principle administered may be up to 50 mg/kg, in one or more individual doses. Parenterally and rectally, it may be up to 10 mg/kg, in one or more individual doses. ##STR4##

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• 1996
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